Edited by: Andrea Malandrino, Massachusetts Institute of Technology, USA
Reviewed by: Jacopo Ferruzzi, Boston University, USA
Specialty section: This article was submitted to Biomechanics, a section of the journal Frontiers in Bioengineering and Biotechnology
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Mechanical forces are powerful regulators of biology and disease. In the vasculature, the expression of particular cellular phenotypes appears to depend not only on a combination of intrinsic genetically programed biology but also on local hemodynamic environmental factors induced by blood flow (Nerem and Girard,
Knowledge gained from mechanobiology could contribute to the development of more effective treatment modalities articulated around two basic strategies.
The effectiveness of a pharmacological treatment depends on the ability to identify potential target molecules involved in the early stage of the disease before the pathology attains a point of no return. Unfortunately, the current state of the science on many cardiovascular disorders still does not permit to support a particular pharmacological target. As it is the case with many cardiovascular pathologies, the sensing of flow abnormalities and their transduction into downstream pathological cascades are the initial triggering events of disease development. The identification of key flow-sensitive molecules responsible for transducing alterations in the surrounding mechanical environment into the initial inflammation and remodeling biological responses would enable the development of targeted, non-invasive pharmacological cellular therapies aimed at blocking the mechanobiological cascade (Figure
While the formation of calcific nodules on the aortic surface of the valve leaflets has been described historically as an age-related degenerative disorder, recent progress in valvular mechanobiology has shed new light on the potential role played by blood flow abnormalities in the early inflammatory precursor events to calcification (Balachandran et al.,
Another potential strategy is to address directly the flow abnormalities responsible for the downstream biological cascade and to reverse the local hemodynamics to its physiologic baseline level. The identification of the specific hemodynamic factors (e.g., WSS magnitude/directionality, pressure) responsible for the pathological response and their normalization could potentially slow down the disease process and limit or completely block its development (Figure
The main mode of failure of hemodialysis vascular access is the progressive occlusion of the vein through which arterial flow is shunted. The initial event leading to stenosis is IH, a disorder causing the thickening of the innermost layer of the vein wall and whose etiology has been associated with the flow disturbances caused by the redirection of the arterial flow through the vein (Glagov,
The success of the strategies outlined above relies on the ability to resolve the mechanobiological processes involved in disease and to translate the knowledge gained into a clinical solution. These points are discussed below and summarized in Table
| Research needs | Hemodynamic characterization | Mechanobiological response elucidation | Clinical translation |
|---|---|---|---|
| Enabling methodologies and technologies |
Computational modeling (CFD, FSI) |
Bioreactor technology (shear stress bioreactors, organ culture systems, microfluidic devices) Tissue/cell cultures Biological assessment (RT-PCR, immunoblotting, immunostaining, zymography) |
Biostatistics Molecular inhibitors identification ( Flow normalization device design and development |
| Challenges |
Patient-specific anatomies and boundary conditions Spatial and temporal resolutions Cost |
Maintenance of sterility Bioreactor level of sophistication Multi-scale biological characterization (cell/tissue-level) |
Drug safety Device thrombogenicity, biocompatibility FDA approval Cost Effectiveness |
The first requirement in mechanobiological studies is the definition of the normal (i.e., baseline) hemodynamic stress state and of the hemodynamic alterations triggering a pathological state. The characterization of blood flow is challenging due to its three-dimensionality, unsteadiness, turbulence, and strong coupling with the surrounding compliant vasculature (Dasi et al.,
The characterization of the biological response following tissue or cell exposure to a particular mechanical signal is another important component of mechanobiology. Typically, cells and tissue specimens have been conditioned mechanically using commercial and in-house bioreactors. While early devices (e.g., parallel flow chamber, pressure chamber) were able to generate only basic mechanical stimuli (e.g., unidirectional steady WSS, steady pressure), current bioreactors are able to mimic more closely the complexity of the native hemodynamic environment. Examples of such devices are single and double cone-and-plate bioreactors to expose vascular tissue to single-sided or double-sided pulsatile WSS (Sucosky et al.,
While mechanobiological studies have already contributed immensely to the understanding of cardiovascular pathologies, only few have been translated into clinical solutions. Major challenges include the complexity of interpretation of biological data, the assessment of the isolated and synergistic roles of mechanosensitive molecules in the disease process, the identification of effective, but safe, molecular inhibitors aimed at blocking the mechanobiological cascade, and the design of effective procedures and devices to normalize blood flow. While those complex issues are still current, the recent realization of the potential use of mechanobiology as a discovery tool for novel treatments and diagnosis modalities has motivated some collaborative efforts between the clinical and engineering fields. Those synergies are necessary to complement the basic science of mechanobiology and to elevate it to effective clinical solutions.
With the continuous progress in flow characterization techniques, bioreactor technologies and biological assessment methodologies, mechanobiology has emerged as a potential tool to deliver the next generation of therapies in cardiovascular disease. The characterization of mechanical cues promoting cardiovascular pathogenesis, the identification and modeling of key mechanosensitive molecules and molecular pathways involved in the early stage of disease, and the integration of this knowledge into patient-specific flow models could provide new therapeutic modalities and predictive capabilities that will transform clinical decision-making and personalized care in cardiovascular medicine.
SA and AM wrote the paper and share first authorship. PS wrote the paper and conceived the work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors would like to thank Midwest Cardiology at St. Joseph Hospital (Mishawaka, IN, USA) and IU School of Medicine at IUPUI (Indianapolis, IN, USA) for providing access to clinical and surgical procedures.
Research described in this paper has been funded by the National Science Foundation (CAREER CMMI-1148558), the American Heart Association (11SDG7600103, 14PRE18940010, and 06POST0625620B), and the National Institutes of Health through the Indiana Clinical and Translational Science Institute (Collaboration in Translational Research Pilot Grant Program).